Agent for prophylaxis and treatment of interstitial pneumonia and pulmonary fibrosis

ABSTRACT

An agent for the prophylaxis and treatment of interstitial pneumonia and pulmonary fibrosis, which contains a compound having a Rho kinase inhibitory activity, particularly an agent for the prophylaxis and treatment of interstitial pneumonia and pulmonary fibrosis, which contains a compound of the formula (I) 
                 
 
wherein each symbol is as defined in the specification, as the compound having a Rho kinase inhibitory activity, is provided.

This application is a 371 of PCT/JP00/01728 filed Mar. 21, 2000.

TECHNICAL FIELD

The present invention relates to an agent for the prophylaxis andtreatment of interstitial pneumonia and pulmonary fibrosis. Morespecifically, the present invention relates to an agent for theprophylaxis and treatment of interstitial pneumonia and pulmonaryfibrosis, which comprises a compound having a Rho kinase inhibitoryactivity as an active ingredient.

BACKGROUND ART

Interstitial pneumonia is an inflammation of lung stroma, which means aninflammation of alveolar wall and peripheral supporting tissue. While itincludes local one and diffuse one, interstitial pneumonia generallymeans diffuse interstitial pneumonia, including acute type and chronictype. Histologically, it is classified into five types of UIP (usual orclassical interstitial pneumonia), BIP (obstructive bronchiolarinterstitial pneumonia), DIP (desquamative interstitial pneumonia), LIP(lymphoid interstitial pneumonia) and GIP (giant cell interstitialpneumonia). Those having an unknown cause are called idiopathicinterstitial pneumonia (XIP) in Japan and idiopathic pulmonary fibrosis(IPF) in US and Europe. Those having a known cause includepneumoconiosis, hypersensitivity pneumonitis, radiation pneumonitis,infection disease and the like. The disease sometimes accompanies asystemic dusease, such as sarcoidosis, histiocytosis X, collagen diseaseand the like. Clinically, dry coughing, exertional dyspnea, fever,clubbing of finger, cyanosis and the like are observed. One associatedwith systemic disease shows other systemic symptoms. The disease showsVelcro rale (fine crackle) by chest auscultation, ground glass opacityin an early stage, then fine particle-like shadow, and orbicular shadowand honeycomb shadow as the disease progresses, by chest X-ray image. Byventilatory function test, restrictive ventilatory defect, diffusiondisturbance and hypoxemia are observed. It is an intractable diseasewith poor prognosis that shows fibrosis or honey cone lung as the finalimage.

Pulmonary fibrosis in interstitial pneumonia is pathologically alveolarseptal tylosis, mainly characterized by growth of type II alveolarepithelial cells and fibroblast, and an increase in the collagen fibersproduced by fibroblast. Its etiology is not certain but involvement ofvarious cytokines is postulated. That is, known cellular groups involvedtherein are fibroblast, smooth muscle cell, hematocyte-derivedmacrophage, lymphocyte, neutrophile, acidocyte and basocyte, all ofwhich constituting the mesenchymal cell, and alveolar epithelial cell,respiratory epithelial cell, vascular endothelial cell and the like asepidermic cells. These cells are activated by inflammatory stimulaionand the like and express various cytokines and the like, and inducechanges in adhesion molecules. By these, pulmonary tissues are damaged,which triggers proliferation of type II alveolar epithelial cell andfibroblast, thereby advancing fibrosis.

Pulmonary fibrosis is a disease where diffuse fibroplasia of alveolarwall is observed, and is mainly characterized by dry coughing andexertional dyspnea. The name of pulmonary fibrosis means the end ofinterstitial pneumonia in a narrow sense, but in a wide sense, it meansconcomitant presence of pulmonary fibrosis in a narrow sense andinterstitial pneumonia. Any interstitial pneumonia can cause thisdisease. It shows noticeable diffuse honeycomb shadow and pulmonaryatrophy by X-ray chest image, and restrictive ventilatory defect,diffusion disturbance and hypoxemia are found by a ventilatory functiontest.

On the other hand, an antitumor agent, bleomycin, is known to cause, asa side effect, diffuse alveolar damage in the acute stage, andinterstitial pneumonia and pulmonary fibrosis in the chronic stage. Inan animal test, too, the administration of bleomycin shows initialimages of interstitial pneumonia in the acute stage, and tylosis ofalveolar wall, growth of type II alveolar cells and fibroblasts in thechronic stage, and many studies have been made as a model of humaninterstitial pneumonia and pulmonary fibrosis.

The conventional main therapy of such interstitial pneumonia andpulmonary fibrosis is administration of a steroid drug against activesymptoms. This agent does not bring about a cure of the disease, butsuppression of activity of the disease and stabilization of diseasestate. Thus, the utility of the drug is open to question. Moreover, aweight loss due to the steroid drug administration frequently inducesacute exacerbation, which, in rare instances, is known to result in adeath, and administration of a steroid drug is considered to beineffective particularly in chronic cases. In the case of sarcoidosis,it is considered to even aggravate the long term prognosis.

Therefore, the creation of a drug aiming at a cure of the disease itselfof the above-mentioned interstitial pneumonia, pulmonary fibrosis andthe like has been awaited.

As a compound having a Rho kinase inhibitory activity, a compound of theformula (I) to be mentioned later has been reported (WO98/06433).Certain isoquinolinesulfonamide derivative and isoquinoline derivativeare also reported to show a Rho kinase inhibitory activity (WO98/06433and Naunyn-Schmiedeberg's Archives of Pharmacology 385(1) Suppl., R219,1998).

The pharmaceutical use of a compound having a Rho kinase inhibitoryactivity is disclosed in WO98/06433, and described to be widely usefulas a therapeutic agent of hypertension, a therapeutic agent of anginapectoris, a cerebrovascular spasm suppressant, a therapeutic agent ofasthma, a therapeutic agent of peripheral circulatory disturbance, apremature delivery preventive, a therapeutic agent of arterialsclerosis, an anticancer drug, an anti-inflammatory agent, animmunosuppressant, a therapeutic agent of autoimmune diseases, ananti-AIDS agent, a therapeutic agent of osteoporosis, a therapeuticagent of retinopathy, a cerebral function improver, a contraceptivedrug, and a gastrointestinal tract infection preventive. On the otherhand, WO98/06433 does not teach its usefulness for the prevention andtreatment of interstitial pneumonia and pulmonary fibrosis, or adescription to suggest such effect.

Furthermore, the compound of formula (I) has been already known to beuseful as an agent for the prophylaxis and treatment of disorders ofcirculatory organs such as coronary, cerebral, renal, peripheral arteryand the like (e.g., a therapeutic agent of hypertension, a therapeuticagent of angina pectoris, a therapeutic agent of renal and peripheralcirculation disorder, a suppressive agent of cerebrovascular contractionand the like), which is potent and long lasting, and also as atherapeutic agent of asthma (JP-A-62-89679, JP-A-3-218356, JPA-4-273821,JP-A-5-194401, JP-A-6-41080 and WO95/28387).

The isoquinolinesulfonamide derivative described in the above-mentionedWO98/06433 is known to be effective as a vasodilating agent, atherapeutic agent of hypertension, a cerebral function improver, ananti-asthma agent, a heart protecting agent, a platelet aggregationinhibitor, a therapeutic agent of neurologic manifestation, ananti-inflammatory agent, an agent for the prevention and treatment ofhyperviscosity syndrome, a therapeutic agent of glaucoma, a diminishedtension agent, a motor paralysis improver of cerebral thorbmbosis, anagent for prevention and treatment of virus infection andtranscriptional control factor inhibitor (JP-A-57-200366,JP-A-61-227581, JP-A-2-256617, JP-A-4-264030, JP-A-6-56668,JP-A-6-80569, JP-A-6-293643, JP-A-7-41424, JP-A-7-277979, WO97/23222,JP-A-9-227381, JP-A-10-45598 and JP-A-10-87491).

Moreover, the isoquinoline derivative described in the above-mentionedpublication (Naunyn-Schmiedeberg's Archives of Pharmacology 385(1)Suppl., R219, 1998) is known to be useful as an agent for the preventionand treatment of brain tissue disorder due to vasospasm (WO97/28130).

However, these compounds having Rho kinase inhibitory activity are notdisclosed to be useful for prophylaxis and treatment of interstitialpneumonia and pulmonary fibrosis, and there is no description suggestiveof such usefulness.

DISCLOSURE OF THE INVENTION

The present invention aims at solving the above-mentioned problems andprovides a novel agent for the prophylaxis and treatment of interstitialpneumonia and pulmonary fibrosis, which is superior in a prophylacticand therapeutic effect on interstitial pneumonia and pulmonary fibrosis.

The present inventors have conducted intensive studies and found that acompound having a Rho kinase inhibitory activity has an effect of theprevention and treatment of interstitial pneumonia and pulmonaryfibrosis, and that it is useful for the prophylaxis and treatment ofinterstitial pneumonia, which resulted in the completion of the presentinvention.

Accordingly, the present invention provides the following.

-   (1) An agent for the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis, which comprises a compound having    a Rho kinase inhibitory activity.-   (2) The agent for the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis of (1) above, wherein the compound    having a Rho kinase inhibitory activity is an amide compound of the    following formula (I)-    wherein    -   Ra is a group of the formula        in the formulas (a) and (b),    -   R is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or        aralkyl, which optionally has a substituent on the ring, or a        group of the formula    -    wherein R⁶ is hydrogen, alkyl or formula: —NR⁸R⁹ wherein R⁸ and        R⁹ are the same or different and each is hydrogen, alkyl,        aralkyl or phenyl, R⁷ is hydrogen, alkyl, aralkyl, phenyl, nitro        or cyano, or R⁶ and R⁷ in combination show a group forming a        heterocycle optionally having, in the ring, oxygen atom, sulfur        atom or optionally substituted nitrogen atom,    -   R¹ is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or        aralkyl, which optionally has a substituent on the ring, or R        and R¹ in combination form, together with the adjacent nitrogen        atom, a group forming a heterocycle optionally having, in the        ring, oxygen atom, sulfur atom or optionally substituted        nitrogen atom,    -   R² is hydrogen or alkyl,    -   R³ and R⁴ are the same or different and each is hydrogen, alkyl,        aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy,        alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio,        aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl        or azide, and    -   A is a group of the formula    -    wherein R¹⁰ and R¹¹ are the same or different and each is        hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or        alkoxycarbonyl, or R¹⁰ and R¹¹ show a group which forms        cycloalkyl in combination and l, m and n are each 0 or an        integer of 1-3,        in the formula (c),    -   L is hydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl,        tetrahydrofurfuryl, carbamoylalkyl, phthalimidoalkyl, amidino or        a group of the formula    -    wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy,        aminoalkyl, hydroxyalkyl, alkanoyloxy-alkyl,        alkoxycarbonylalkyl, α-aminobenzyl, furyl, pyridyl, phenyl,        phenylamino, styryl or imidazopyridyl,        -   Q¹ is hydrogen, halogen, hydroxy, aralkyloxy or            thienylmethyl,        -   W is alkylene,        -   Q² is hydrogen, halogen, hydroxy or aralkyloxy,        -   X is alkylene,        -   Q³ is hydrogen, halogen, hydroxy, alkoxy, nitro, amino,        -   2,3-dihydrofuryl or            5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl;        -   and Y is a single bond, alkylene or alkenylene, and            in the formula (c),    -   a broken line is a single bond or a double bond, and    -   R⁵ is hydrogen, hydroxy, alkoxy, alkoxycarbonyloxy, alkanoyloxy        or aralkyloxycarbonyloxy;    -   Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono-        or dialkylaminoalkyl; and    -   Rc is an optionally substituted heterocycle containing nitrogen,        an isomer thereof and/or a pharmaceutically acceptable acid        addition salt thereof.-   (3) The agent for the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis of (1) or (2) above, wherein the    compound having a Rho kinase inhibitory activity is an amide    compound of the following formula (I′)-    wherein    -   Ra′ is a group of the formula    -    wherein    -   R′ is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or        aralkyl, which optionally has a substituent on the ring,    -   R¹ is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or        aralkyl, which optionally has a substituent on the ring, or R′        and R¹ in combination form, together with the adjacent nitrogen        atom, a group forming a heterocycle optionally having, in the        ring, oxygen atom, sulfur atom or optionally substituted        nitrogen atom,    -   R² is hydrogen or alkyl,    -   R³ and R⁴ are the same or different and each is hydrogen, alkyl,        aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy,        alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio,        aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl        or azide, and    -   A is a group of the formula    -    wherein R¹⁰ and R¹¹ are the same or different and each is        hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or        alkoxycarbonyl, or R¹⁰ and R¹¹ show a group which forms        cycloalkyl in combination and l, m and n are each 0 or an        integer of 1-3,    -   Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono-        or dialkylaminoalkyl; and    -   Rc is an optionally substituted heterocycle containing nitrogen,        an isomer thereof and/or a pharmaceutically acceptable acid        addition salt thereof.-   (4) The agent for the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis of (1) above, wherein the compound    having a Rho kinase inhibitory activity is a compound selected from    the group consisting of    (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane,    (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide,    (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and    (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide,    and/or a pharmaceutically acceptable acid addition salt thereof.-   (5) The agent for the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis of (1) above, wherein the compound    having a Rho kinase inhibitory activity is    (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and/or    a pharmaceutically acceptable acid addition salt thereof.-   (6) A pharmaceutical composition for the prophylaxis and treatment    of interstitial pneumonia and pulmonary fibrosis, which comprises a    compound having a Rho kinase inhibitory activity and a    pharmaceutically acceptable carrier.-   (7) The pharmaceutical composition for the prophylaxis and treatment    of interstitial pneumonia and pulmonary fibrosis of (6) above,    wherein the compound having a Rho kinase inhibitory activity is an    amide compound of the formula (I), an isomer thereof and/or a    pharmaceutically acceptable acid addition salt thereof.-   (8) The pharmaceutical composition for the prophylaxis and treatment    of interstitial pneumonia and pulmonary fibrosis of (6) or (7),    wherein the compound having a Rho kinase inhibitory activity is an    amide compound of the formula (I′), an isomer thereof and/or a    pharmaceutically acceptable acid addition salt thereof.-   (9) The pharmaceutical composition for the prophylaxis and treatment    of interstitial pneumonia and pulmonary fibrosis of (6) above,    wherein the compound having a Rho kinase inhibitory activity is a    compound selected from the group consisting of    (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane,    (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide,    (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and    (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide,    and/or a pharmaceutically acceptable acid addition salt thereof.-   (10) The pharmaceutical composition for the prophylaxis and    treatment of interstitial pneumonia and pulmonary fibrosis of (6)    above, wherein the compound having a Rho kinase inhibitory activity    is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane    and/or a pharmaceutically acceptable acid addition salt thereof.-   (11) A method of the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis, which comprises administering an    effective amount of a compound having a Rho kinase inhibitory    activity to a patient.-   (12) The method of the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis of (11) above, wherein the compound    having a Rho kinase inhibitory activity is an amide compound of the    formula (I), an isomer thereof and/or a pharmaceutically acceptable    acid addition salt thereof.-   (13) The method of the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis of (11) or (12) above, wherein the    compound having a Rho kinase inhibitory activity is an amide    compound of the formula (I′), an isomer thereof and/or a    pharmaceutically acceptable acid addition salt thereof.-   (14) The method of the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis of (11) above, wherein the compound    having a Rho kinase inhibitory activity is a compound selected from    the group consisting of    (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane,    (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide,    (R)-(+)-N-(4-pyridyl-4-(1-aminoethyl)benzamide and    (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide,    and/or a pharmaceutically acceptable acid addition salt thereof.-   (15) The method of the prophylaxis and treatment of interstitial    pneumonia and pulmonary fibrosis of (11) above, wherein the compound    having a Rho kinase inhibitory activity is a    (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, and/or    a pharmaceutically acceptable acid addition salt thereof.-   (16) Use of a compound having a Rho kinase inhibitory activity for    the production of an agent for the prophylaxis and treatment of    interstitial pneumonia and pulmonary fibrosis.-   (17) The use of (16) above, wherein the compound having a Rho kinase    inhibitory activity is an amide compound of the following formula    (I), an isomer thereof and/or a pharmaceutically acceptable acid    addition salt thereof.-   (18) The use of (16) or (17) above, wherein the compound having a    Rho kinase inhibitory activity is an amide compound of the following    formula (I′), an isomer thereof and/or a pharmaceutically acceptable    acid addition salt thereof.-   (19) The use of (16) above, wherein the compound having a Rho kinase    inhibitory activity is a compound selected from the group consisting    of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane,    (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide,    (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and    (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide,    and/or a pharmaceutically acceptable acid addition salt thereof.-   (20) The use of (16) above, wherein the compound having a Rho kinase    inhibitory activity is a    (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, and/or    a pharmaceutically acceptable acid addition salt thereof.-   (21) A commercial package comprising a pharmaceutical composition    for the prophylaxis and treatment of interstitial pneumonia and    pulmonary fibrosis of any of (6) to (10) above, and a written matter    associated therewith, the written matter stating that the    pharmaceutical composition can or should be used for the prophylaxis    and treatment of interstitial pneumonia and pulmonary fibrosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the expression amount of a ROCK-II gene in amodel with bleomycin-induced interstitial pneumonia (pulmonaryfibrosis), wherein the axis of ordinates shows relative expressionamount of the ROCK-II gene (ROCK-II mRNA/GAPDH mRNA), the axis ofabscissas shows the time (days) after bleomycin administration, □ showsa bleomycin non-administration group and ▪ shows a bleomycinadministration group (total amount of administration 200 mg/kg), (n=4,*p<0.05).

FIG. 2 is a graph showing the effect of the compound of the presentinvention (Y-27632) on the number of inflammatory cells inbronchoalveolar lavage of a model with bleomycin-induced interstitialpneumonia (pulmonary fibrosis), wherein the axis of ordinates shows thenumber of cells of respective kinds of inflammatory cells, the axis ofabscissas shows the time (days) after bleomycin administration, □ showsa group (BLM group) administered with bleomycin and physiological salineevery other day, ◯ shows a group (Y-27632 group) administered withbleomycin and Y-27632 every other day, and Δ shows a group (Normalgroup) not administered with bleomycin but with physiological salineevery other day (n=5, *p<0.05; BLM group vs Y-27632 group, § p<0.05; BLMgroup vs Normal group, +p<0.05; Y-27632 group vs Normal group).

FIG. 3 is a graph showing the action of the compound of the presentinvention (Y-27632) on cell chemotaxis, wherein the axis of ordinatesshows the number of migrated cell and the axis of abscissas shows theconcentration of Y-27632 (n=6, *p<0.05 Y-27632-untreated group vsY-27632-treated group).

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, by the “interstitial pneumonias” is meant aninflammation of lung stroma, which refers to an inflammation of alveolarwall and peripheral supporting tissue. While it includes local one anddiffuse one, interstitial pneumonia generally refers to diffuseinterstitial pneumonia, including acute type and chronic type.Histologically, it is classified into 5 types of UIP (usual or classicalinterstitial pneumonia), BIP (obstructive bronchiolar interstitialpneumonia), DIP (desquamative interstitial pneumonia), LIP (lymphoidinterstitial pneumonia) and GIP (giant cell interstitial pneumonia). Thedisease whose cause is unknown is referred to as idiopathic interstitialpneumonia (IIP). One with clarified cause is referred to aspneumoconiosis, hypersensitivity pneumonitis, radiation pneumonitis,infection disease and the like. The disease may accompany a systemicdisease such as sarcoidosis, histiocytosis X, collagen disease and thelike. Clinically, dry coughing, exertional dyspnea, fever, clubbing offinger, cyanosis and the like are observed, and one accompanying asystemic disease may show other systemic symptoms. The disease showsVelcro rale (fine crackle) by chest auscultation, ground glass opacityin an early stage, then fine particle-like shadow, and orbicular shadowand honeycomb shadow as the disease progresses, by chest X-ray image. Byventilatory function test, restrictive ventilatory defect, diffusiondisturbance and hypoxemia are observed.

In the present invention, the pulmonary fibrosis means a disease wherediffuse fibroplasias of the alveolar wall is found and the main symptomsare dry coughing and exertional dyspnea. While the name of pulmonaryfibrosis means terminal interstitial pneumonia in a narrow sense,pulmonary fibrosis of the present invention refers to one in a widesense, concurrently including pulmonary fibrosis in a narrow sense andinterstitial pneumonia. Any interstitial pneumonia can cause thisdisease. In a chest X-ray image, diffuse honeycomb shadow and pulmonaryatrophy are noticeable, and in a ventilatory function test, restrictiveventilatory defect, diffusion disturbance and hypoxemia are observed.

In the present invention, Rho kinase means serine/threonine kinaseactivated along with the activation of Rho. For example, ROKα (ROCKII:Leung, T. et al, J. Biol. Chem., 270, 29051-29054, 1995), p160 ROCK(ROKβ, ROCK-I: Ishizaki, T. et al, The EMBO J., 15(8), 1885-1893, 1996)and other proteins having a serine/threonine kinase activity areexemplified.

The compound having a Rho kinase inhibitory activity, which is used asan active ingredient in the present invention, may be any as long as ithas a Rho kinase inhibitory activity. Specifically, there are mentionedamide compound, isoquinolinesulfonamide derivative and isoquinolinederivative described in the above-mentioned WO98/06433 and WO97/28130[particularly Naunyn-Schmiedeberg's Archives of Pharmacology 385(1)Suppl., R219, 1998].

As the aforementioned amide compound, for example, a compound of theabove-mentioned formula (I), particularly a compound of the formula(I′), are used. As the aforementioned isoquinolinesulfonic acidderivative, fasudil hydrochloride[hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine] and the like areused. As the aforementioned isoquinoline derivative,hexahydro-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepinedihydrochloride,(S)-(+)-hexahydro-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepinehydrochloride,hexahydro-7-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepinedihydrochloride,hexahydro-5-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepinedihydrochloride,hexahydro-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepinehydrochloride,(R)-(−)-hexahydro-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepinehydrochloride,(R)-(+)-hexahydro-5-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepinehydrochloride and the like are used.

Preferably, an amide compound of the formula (I), particularlypreferably an amide compound of the formula (I′), is used.

In the present invention, one kind of a compound having a Rho kinaseinhibitory activity may be used alone, or, where necessary, severalkinds may be concurrently used.

In the present specification, each symbol of the formulas (I) and (I′)is defined as follows.

Alkyl at R, R′ and R¹ is linear or branched alkyl having 1 to 10 carbonatoms, which is exemplified by methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl and the like, with preference given to alkyl having 1 to 4 carbonatoms.

Cycloalkyl at R, R′ and R¹ has 3 to 7 carbon atoms and is exemplified bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike.

Cycloalkylalkyl at R, R′ and R¹ is that wherein the cycloalkyl moiety isthe above-mentioned cycloalkyl having 3 to 7 carbon atoms and the alkylmoiety is linear or branched alkyl having 1 to 6 carbon atoms (e.g.,methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like),which is exemplified by cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclopropylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl,cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl,cycloheptylpropyl, cyclopropylbutyl, cyclopentylbutyl, cyclohexylbutyl,cycloheptylbutyl, cyclopropylhexyl, cyclopentylhexyl, cyclohexylhexyl,cycloheptylhexyl and the like.

Aralkyl at R, R′ and R¹ is that wherein alkyl moiety is alkyl having 1to 4 carbon atoms and is exemplified by phenylalkyl such as benzyl,1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl and thelike.

The substituent of optionally substituted cycloalkyl, cycloalkylalkyl,phenyl and aralkyl on the ring at R, R′ and R¹ is halogen (e.g.,chlorine, bromine, fluorine and iodine), alkyl (same as alkyl at R, R′and R¹), alkoxy (linear or branched alkoxy having 1 to 6 carbon atoms,such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like), aralkyl(same as aralkyl at R, R′ and R¹) or haloalkyl (alkyl at R, R′ and R¹which is substituted by 1-5 halogen, and exemplified by fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2,3,3,3-pentafluoropropyl and the like), nitro, amino, cyano, azideand the like.

The group formed by R and R′ or R′ and R¹ in combination together withthe adjacent nitrogen atom, which forms a heterocycle optionally having,in the ring, oxygen atom, sulfur atom or optionally substituted nitrogenatom is preferably a 5 or 6-membered ring and bonded ring thereof.Examples thereof include 1-pyrrolidinyl, piperidino, 1-piperazinyl,morpholino, thiomorpholino, 1-imidazolyl, 2,3-dihydrothiazol-3-yl andthe like. The substituent of the optionally substituted nitrogen atom isexemplified by alkyl, aralkyl, haloalkyl and the like. As used herein,alkyl, aralkyl and haloalkyl are as defined for R, R′ and R¹.

Alkyl at R² is as defined for R, R′ and R¹.

Halogen, alkyl, alkoxy and aralkyl at R3 and R⁴ are as defined for R, R′and R¹.

Acyl at R³ and R⁴ is alkanoyl having 2 to 6 carbon atoms (e.g., acetyl,propionyl, butyryl, valeryl, pivaloyl and the like), benzoyl orphenylalkanoyl wherein the alkanoyl moiety has 2 to 4 carbon atoms(e.g., phenylacetyl, phenylpropionyl, phenylbutyryl and the like).

Alkylamino at R³ and R⁴ is that wherein the alkyl moiety is alkylaminohaving linear or branched alkyl having 1 to 6 carbon atoms. Examplesthereof include methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino,hexylamino and the like.

Acylamino at R³ and R⁴ is that wherein acyl moiety is alkanoyl having 2to 6 carbon atoms, benzyl or the alkanoyl moiety is phenylalkanoylhaving 2 to 4 carbon atoms and the like, which is exemplified byacetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino,benzoylamino, phenylacetylamino, phenylpropionylamino,phenylbutyrylamino and the like.

Alkylthio at R³ and R⁴ is that wherein the alkyl moiety is linear orbranched alkyl having 1 to 6 carbon atoms, which is exemplified bymethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio andthe like.

Aralkyloxy at R³ and R⁴ is that wherein the alkyl moiety is alkyl having1 to 4 carbon atoms, which is exemplified by benzyloxy,1-phenylethyloxy, 2-phenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxyand the like.

Aralkylthio at R³ and R⁴ is that wherein the alkyl moiety is alkylhaving 1 to 4 carbon atoms, which is exemplified by benzylthio,1-phenylethylthio, 2-phenylethylthio, 3-phenylpropylthio,4-phenylbutylthio and the like.

Alkoxycarbonyl at R³ and R⁴ is that wherein the alkoxy moiety is linearor branched alkoxy having 1 to 6 carbon atoms, which is exemplified bymethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

Alkylcarbamoyl at R³ and R⁴ is carbamoyl mono- or di-substituted byalkyl having 1 to 4 carbon atoms, which is exemplified bymethylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl,propylcarbamoyl, dipropylcarbamoyl, butylcarbamoyl, dibutylcarbamoyl andthe like.

Alkoxy at R⁵ is as defined for R, R′ and R¹.

Alkoxycarbonyloxy at R⁵ is that wherein the alkoxy moiety is linear orbranched alkoxy having 1 to 6 carbon atoms, which is exemplified bymethoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy,sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy,hexyloxycarbonyloxy and the like.

Alkanoyloxy at R⁵ is that wherein the alkanoyl moiety is alkanoyl having2 to 6 carbon atoms, which is exemplified by acetyloxy, propionyloxy,butyryloxy, valeryloxy, pivaloyloxy and the like.

Aralkyloxycarbonyloxy at R⁵ is that wherein the aralkyl moiety isaralkyl having C₁-C₄ alkyl, which is exemplified bybenzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy,2-phenylethyloxycarbonyloxy, 3-phenylpropyloxycarbonyloxy,4-phenylbutyloxycarbonyloxy and the like.

Alkyl at R⁶ is as defined for R, R′ and R¹; alkyl at R⁸ and R⁹ is asdefined for R, R′ and R¹; and aralkyl at R⁸ and R⁹ is as defined for R,R′ and R¹.

Alkyl at R⁷ is as defined for R, R′ and R¹ and aralkyl at R⁷ is asdefined for R, R′ and R¹.

The group formed by R⁶ and R⁷ in combination, which forms a heterocycleoptionally having, in the ring, oxygen atom, sulfur atom or optionallysubstituted nitrogen atom, is imidazol-2-yl, thiazol-2-yl, oxazol-2-yl,imidazolin-2-yl, 3,4,5,6-tetrahydropyridin-2-yl,3,4,5,6-tetrahydropyrimidin-2-yl, 1,3-oxazolin-2-yl, 1,3-thiazolin-2-ylor optionally substituted benzoimidazol-2-yl, benzothiazol-2-yl,benzoxazol-2-yl and the like having a substituent such as halogen,alkyl, alkoxy, haloalkyl, nitro, amino, phenyl, aralkyl and the like. Asused herein, halogen, alkyl, alkoxy, haloalkyl and aralkyl are asdefined for R, R′ and R¹.

The substituent of the above-mentioned optionally substituted nitrogenatom is exemplified by alkyl, aralkyl, haloalkyl and the like. As usedherein, alkyl, aralkyl and haloalkyl are as defined for R, R′ and R¹.

Hydroxyalkyl at R¹⁰ and R¹¹ is linear or branched alkyl having 1 to 6carbon atoms which is substituted by 1 to 3 hydroxy, which isexemplified by hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl and the like.

Alkyl at R¹⁰ and R¹¹ is as defined for R, R′ and R¹; haloalkyl andalkoxycarbonyl at R¹⁰ and R¹¹ are as defined for R, R′ and R¹; aralkylat R¹⁰ and R¹¹ is as defined for R, R′ and R¹.

Cycloalkyl formed by R¹⁰ and R¹¹ in combination is the same ascycloalkyl at R, R′ and R¹.

Alkyl at L is as defined for R, R′ and R¹.

Aminoalky at L is a linear or branched alkyl having 1 to 6 carbon atoms,which is substituted by amino, which is exemplified by aminomethyl,2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl,6-aminohexyl and the like.

Mono- or dialkylaminoalkyl at L is mono- or di-substituted aminoalkylwith alkyl having 1 to 4 carbon atoms, which is exemplified bymethylaminomethyl, dimethylaminomethyl, ethylaminomethyl,diethylaminomethyl, propylaminomethyl, dipropylaminomethyl,butylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl,2-diethylaminoethyl and the like.

Carbamoylalkyl at L is linear or branched alkyl having 1 to 6 carbonatoms substituted by carbamoyl, which is exemplified by carbamoylmethyl,2-carbamoylethyl, 1-carbamoylethyl, 3-carbamoylpropyl, 4-carbamoylbutyl,5-carbamoylpentyl, 6-carbamoylhexyl and the like.

Phthalimidoalkyl at L is linear or branched alkyl having 1 to 6 carbonatoms, which is substituted by phthalimide. Examples thereof includephthalimidomethyl, 2-phthalimidoethyl, 1-phthalimidoethyl,3-phthalimidopropyl, 4-phthalimidobutyl, 5-phthalimidopentyl,6-phthalimidohexyl and the like.

Alkyl at B is as defined for R, R′ and R¹.

Alkoxy at B is as defined for R, R′ and R¹.

Aralkyl at B is as defined for R, R′ and R¹.

Aralkyloxy at B is as defined for R³ and R⁴.

Aminoalkyl at B is as defined for L.

Hydroxyalkyl at B is as defined for R¹⁰ and R¹¹.

Alkanoyloxyalkyl at B is that wherein linear or branched alkyl having 1to 6 carbon atoms is substituted by alkanoyloxy having alkanoyl moietyhaving 2 to 6 carbon atoms, which is exemplified by acetyloxymethyl,propionyloxymethyl, butyryloxymethyl, valeryloxymethyl,pivaloyloxymethyl, acetyloxyethyl, propionyloxyethyl, butyryloxyethyl,valeryloxyethyl, pivaloyloxyethyl and the like.

Alkoxycarbonylalkyl at B is that wherein linear or branched alkyl having1 to 6 carbon atoms is substituted by alkoxycarbonyl having alkoxymoiety having 1 to 6 carbon atoms, which is exemplified bymethoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl,isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl,sec-butoxycarbonylmethyl, tert-butoxycarbonylmethyl,pentyloxycarbonylmethyl, hexyloxycarbonylmethyl, methoxycarbonylethyl,ethoxycarbonylethyl, propoxycarbonylethyl, isopropoxycarbonylethyl,butoxycarbonylethyl, isobutoxycarbonylethyl, sec-butoxycarbonylethyl,tert-butoxycarbonylethyl, pentyloxycarbonylethyl, hexyloxycarbonylethyland the like.

Halogen at Q¹, Q² and Q³ is as defined for R, R′ and R¹.

Aralkyloxy at Q¹ and Q² is as defined for R³ and R⁴.

Alkoxy at Q³ is as defined for R, R′ and R¹.

Alkylene at W, X and Y is linear or branched alkylene having 1 to 6carbon atoms, which is exemplified by methylene, ethylene, trimethylene,propylene, tetramethylene, pentamethylene, hexamethylene and the like.

Alkenylene at Y is linear or branched alkenylene having 2 to 6 carbonatoms, which is exemplified by vinylene, propenylene, butenylene,pentenylene and the like.

Alkyl at Rb is as defined for R, R′ and R¹.

Aralkyl at Rb is as defined for R, R′ and R¹.

Aminoalkyl at Rb is as defined for L.

Mono- or dialkylaminoalkyl at Rb is as defined for L.

The nitrogen-containing heteromonocycle at Rc is pyridine, pyrimidine,pyridazine, triazine, pyrazole, triazole and the like, and when it is acondensed ring, it is exemplified by pyrrolopyridine (e.g.,1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine,1H-pyrrolo[3,4-b]pyridine and the like), pyrazolopyridine (e.g.,1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[4,3-b]pyridine and the like),imidazopyridine (e.g., 1H-imidazo[4,5-b]pyridine and the like),pyrrolopyrimidine (e.g., 1H-pyrrolo[2,3-d]pyrimidine,1H-pyrrolo[3,2-d]pyrimidine, 1H-pyrrolo[3,4-d]pyrimidine and the like),pyrazolopyrimidine (e.g., 1H-pyrazolo[3,4-d]pyrimidine,pyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[4,3-d]pyrimidine and the like),imidazopyrimidine (e.g., imidazo[1,2-a]pyrimidine,1H-imidazo[4,5-d]pyrimidine and the like), pyrrolotriazine (e.g.,pyrrolo[1,2-a]-1,3,5-triazine, pyrrolo[2,1-f]-1,2,4-triazine),pyrazolotriazine (e.g., pyrazolo[1,5-a]-1,3,5-triazine and the like),triazolopyridine (e.g., 1H-1,2,3-triazolo[4,5-b]pyridine and the like),triazolopyrimidine (e.g., 1,2,4-triazolo[1,5-a]pyrimidine,1,2,4-triazolo[4,3-a]pyrimidine, 1H-1,2,3-triazolo[4,5-d]pyrimidine andthe like), cinnoline, quinazoline, quinoline, pyridopyridazine (e.g.,pyrido[2,3-c]pyridazine and the like), pyridopyrazine (e.g.,pyrido[2,3-b]pyrazine and the like), pyridopyrimidine (e.g.,pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine and the like),pyrimidopyrimidine (e.g., pyrimido[4,5-d]pyrimidine,pyrimido[5,4-d]pyrimidine and the like), pyrazinopyrimidine (e.g.,pyrazino[2,3-d]pyrimidine and the like), naphthyridine (e.g.,1,8-naphthyridine and the like), tetrazolopyrimidine (e.g.,tetrazolo[1,5-a]pyrimidine and the like), thienopyridine (e.g.,thieno[2,3-b]pyridine and the like), thienopyrimidine (e.g.,thieno[2,3-d]pyrimidine and the like), thiazolopyridine (e.g.,thiazolo[4,5-b]pyridine, thiazolo[5,4-b]pyridine and the like),thiazolopyrimidine (e.g., thiazolo[4,5-d]pyrimidine,thiazolo[5,4-d]pyrimidine and the like), oxazolopyridine (e.g.,oxazolo[4,5-b]pyridine, oxazolo[5,4-b]pyridine and the like),oxazolopyrimidine (e.g., oxazolo[4,5-d]pyrimidine,oxazolo[5,4-d]pyrimidine and the like), furopyridine (e.g.,furo[2,3-b]pyridine, furo[3,2-b]pyridine and the like), furopyrimidine(e.g., furo[2,3-d]pyrimidine, furo[3,2-d]pyrimidine and the like),2,3-dihydropyrrolopyridine (e.g., 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine,2,3-dihydro-1H-pyrrolo[3,2-b]pyridine and the like),2,3-dihydropyrrolopyrimidine (e.g.,2,3-dihydro-1H-pyrrolo[2,3-d]pyrimidine,2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidine and the like),5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine,5,6,7,8-tetrahydro-1,8-naphthyridine, 5,6,7,8-tetrahydroquinoline andthe like. When these rings form a hydrogenated aromatic ring, the carbonatom in the ring may be carbonyl and includes, for example,2,3-dihydro-2-oxopyrrolopyridine, 2,3-dihydro-2,3-dioxopyrrolopyridine,7,8dihydro-7-oxo-1,8-naphthyridine,5,6,7,8-tetrahydro-7-oxo-1,8-naphthyridine and the like.

These rings may be substituted by a substituent such as halogen, alkyl,alkoxy, aralkyl, haloalkyl, nitro, amino, alkylamino, cyano, formyl,acyl, aminoalkyl, mono- or dialkylaminoalkyl, azide, carboxy,alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkoxyalkyl (e.g.,methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl,ethoxypropyl and the like), optionally substituted hydrazino and thelike.

As used herein, the substituent of the optionally substituted hydrazinoincludes alkyl, aralkyl, nitro, cyano and the like, wherein alkyl andaralkyl are as defined for R, R′ and R¹ and exemplified bymethylhydrazino, ethylhydrazino, benzylhydrazino and the like.

The compound of the formula (I) is exemplified by the followingcompounds.

-   (1) 4-(2-pyridylcarbamoyl)piperidine-   (2) 1-benzyloxycarbonyl-4-(4-pyridylcarbamoyl)piperidine-   (3) 1-benzoyl-4-(4-pyridylcarbamoyl)piperidine-   (4) 1-propyl-4-(4-pyridylcarbamoyl)piperidine-   (5)    1-[3-(2-(2-thienylmethyl)phenoxy)-2-hydroxyproply]-4(4-pyridylcarbamoyl)piperidine-   (6) 4-(4-pyridylcarbamoyl)piperidine-   (7) 1-benzyl-4-(4-pyridylcarbamoyl)-1,2,5,6-tetrahydropyridine-   (8) 3-(4-pyridylcarbamoyl)piperidine-   (9) 1-benzyl-3-(4-pyridylcarbamoyl)piperidine-   (10)    1-(2-(4-benzyloxyphenoxy)ethyl)-4-(N-(2-pyridyl)-N-benzylcarbamoyl)pyridine-   (11) 1-formyl-4-(4-pyridylcarbamoyl)piperidine-   (12) 4-(3-pyridylcarbamoyl)piperidine-   (13) 1-isopropyl-4-(4-pyridylcarbamoyl)piperidine-   (14) 1-methyl-4-(4-pyridylcarbamoyl)piperidine-   (15) 1-hexyl-4-(4-pyridylcarbamoyl)piperidine-   (16) 1-benzyl-4-(4-pyridylcarbamoyl)piperidine-   (17) 1-(2-phenylethyl)-4-(4-pyridylcarbamoyl)piperidine-   (18) 1-(2-(4-methoxyphenyl)ethyl)-4-(4-pyridylcarbamoyl)piperidine-   (19) 1-(2-(4-methoxyphenyl)ethyl)-4-(2-pyridylcarbamoyl)piperidine-   (20) 1-(2-(4-chlorophenyl)ethyl)-4-(4-pyridylcarbamoyl)piperidine.-   (21) 1-diphenylmethyl-4-(2-pyridylcarbamoyl)piperidine-   (22)    1-[2-(4-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)phenyl)ethyl]-4-(2-pyridylcarbamoyl)piperidine-   (23)    1-(4-(4,5-dihydro-2-furyl)phenyl)-4-(4-pyridylcarbamoyl)piperidine-   (24) 1-(2-nitrophenyl)-4-(4-pyridylcarbamoyl)piperidine-   (25) 1-(2-aminophenyl)-4-(4-pyridylcarbamoyl)piperidine-   (26) 1-nicotinoyl-4-(4-pyridylcarbamoyl)piperidine-   (27) 1-isonicotinoyl-4-(4-pyridylcarbamoyl)piperidine-   (28) 1-(3,4,5-trimethoxybenzoyl)-4-(4-pyridylcarbamoyl)piperidine-   (29) 1-acetyl-4-(4-pyridylcarbamoyl)piperidine-   (30) 1-(3-(4-fluorobenzoyl)propyl)-4-(4-pyridylcarbamoyl)piperidine-   (31) 1-(3-(4-fluorobenzoyl)propyl)-4-(2-pyridylcarbamoyl)piperidine-   (32) 1-(1-(4-hydroxybenzoyl)ethyl)-4-(2-pyridylcarbamoyl)piperidine-   (33)    1-(1-(4-benzyloxybenzoyl)ethyl)-4-(2-pyridylcarbamoyl)piperidine-   (34) 1-(2-(4-hydroxyphenoxy)ethyl)-4-(2-pyridylcarbamoyl)piperidine-   (35)    1-(4-(4-fluorophenyl)-4-hydroxybutyl)-4-(4-pyridylcarbamoyl)piperidine-   (36)    1-(1-methyl-2-(4-hydroxyphenyl)-2-hydroxyethyl)-4-(2-pyridylcarbamoyl)piperidine-   (37) 1-cinnamyl-4-(2-pyridylcarbamoyl)piperidine-   (38) 1-(2-hydroxy-3-phenoxypropyl)-4-(4-pyridylcarbamoyl)piperidine-   (39) 1-(2-hydroxy-3-phenoxypropyl)-4-(3-pyridylcarbamoyl)piperidine-   (40) 1-(2-hydroxy-3-phenoxypropyl)-4-(2-pyridylcarbamoyl)piperidine-   (41)    1-(2-phenylethyl)-4-[N-(2-pyridyl)-N-(2-(N,N-dimethylamino)ethyl)carbamoyl]piperidine-   (42) 1-benzyloxycarbonyl-4-(2-pyridylcarbamoyl)piperidine-   (43) 1-(3-chlorophenyl)carbamoyl-4-(4-pyridylcarbamoyl)piperidine-   (44)    4-[N-(2-pyridyl)-N-(2-(N,N-dimethylamino)ethyl)carbamoyl]piperidine-   (44)    4-[N-(2-pyridyl)-N-(2-(N,N-dimethylamino)ethyl)carbamoyl]piperidine-   (45) 1-methyl-4-(4-pyridylcarbamoyl)-1,2,5,6-tetrahydropyridine-   (46) 1-nicotinoyl-3-(4-pyridylcarbamoyl)piperidine-   (47) 1-[2-(4-fluorobenzoyl)ethyl]-4-(4-pyridylcarbamoyl)piperidine-   (48)    1-(6-chloro-2-methylimidazo[1,2-a]pyridine-3-carbonyl)-4-(4-pyridylcarbamoyl)piperidine-   (49) 1-(4-nitrobenzyl)-4-(4-pyridylcarbamoyl)piperidine-   (50) 1-hexyl-4-(4-pyridylcarbamoyl)piperidine-   (51) 1-benzyloxycarbonyl-4-(2-chloro-4-pyridylcarbamoyl)piperidine-   (52) 4-(2-chloro-4-pyridylcarbamoyl)piperidine-   (53) 1-(2-chloronicotinoyl)-4-(4-pyridylcarbamoyl)piperidine-   (54) 3-(2-chloro-4-pyridylcarbamoyl)piperidine-   (55) 1-(4-phthalimidobutyl)-4-(4-pyridylcarbamoyl)piperidine-   (56)    1-(3,5di-tert-butyl-4-hydroxycinnamoyl)-4-(4-pyridylcarbamoyl)piperidine-   (57) 1-carbamoylmethyl-4-(4-pyridylcarbamoyl)piperidine-   (58) 1-benzyloxycarbonyl-4-(5-nitro-2-pyridylcarbamoyl)piperidine-   (59) 4-(5-nitro-2-pyridylcarbamoyl)piperidine-   (60)    trans-4-benzyloxycarboxamidomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (61) trans-4-aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (62) trans-4-formamidomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (63) trans-4-dimethylaminomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (64) N-benzylidene-trans-(4-pyridylcarbamoyl)cyclohexylmethylamine-   (65) trans-4-benzylaminomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (66) trans-4-isopropylaminomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (67) trans-4-nicotinoylaminomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (68) trans-4-cyclohexylaminomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (69) trans-4-benzyloxycarboxamide-1-(4-pyridylcarbamoyl)cyclohexane-   (70) trans-4-amino-1-(4-pyridylcarbamoyl)cyclohexane-   (71) trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (72)    trans-4-aminomethyl-cis-2-methyl-1-(4-pyridylcarbamoyl)cyclohexane-   (73)    (+)-trans-4-(1-benzyloxycarboxamidopropyl)-1-cyclohexanecarboxylic    acid-   (74)    (+)-trans-4-(1-benzyloxycarboxamidopropyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (75)    (−)-trans-4-(1-benzyloxycarboxamidpropyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (76) (+)-trans-4-(1-aminopropyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (77) (−)-trans-4-(1-aminopropyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (78)    (−)-trans-4-(1-benzyloxycarboxamidoethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (79)    (+)-trans-4-(1-benzyloxycarboxamidoethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (80) (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (81) (−)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (82)    trans-4-(4-chlorobenzoyl)aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (83) trans-4-aminomethyl-1-(2-pyridylcarbamoyl)cyclohexane-   (84)    trans-4-benzyloxycarboxamidomethyl-1-(2-pyridylcarbamoyl)cyclohexane-   (85) trans-4-methylaminomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (86)    trans-4-(N-benzyl-N-methylamino)methyl-1-(4-pyridylcarbamoyl)cyclohexane-   (87) trans-4-aminomethyl-1-(3-pyridylcarbamoyl)cyclohexane-   (88)    trans-4-aminomethyl-1-[(3-hydroxy-2-pyridyl)carbamoyl]cyclohexane-   (89)    trans-4-benzyloxycarboxamidomethyl-1-(3-pyridylcarbamoyl)cyclohexane-   (90)    trans-4-benzyloxycarboxamidomethyl-1-[(3-benzyloxy-2-pyridyl)carbamoyl]cyclohexane-   (91) trans-4-phthalimidomethyl-1-(4-pyridylcarbamoyl)cyclohexane-   (92)    trans-4-benzyloxycarboxamidomethyl-1-(3-methyl-4-pyridylcarbamoyl)cyclohexane-   (93) trans-4-aminomethyl-1-(3-methyl-4-pyridylcarbamoyl)cyclohexane-   (94)    4-(trans-4-benzyloxycarboxamidomethylcyclohexylcarbonyl)-amino-2,6-dimethylpyridine-N-oxide-   (95)    4-(trans-4-aminomethylcyclohexylcarbonyl)amino-2,6-dimethylpyridine-N-oxide-   (96) trans-4-aminomethyl-1-(2-methyl-4-pyridylcarbamoyl)cyclohexane-   (97)    trans-4-(1-benzyloxycarboxamidoethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (98)    trans-4-(1-amino-1-methylethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (99) trans-4-(2-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (100)    trans-4-(2-amino-1-methylethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (101) trans-4-(1-aminopropyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (102)    trans-4-aminomethyl-trans-1-methyl-1-(4-pyridylcarbamoyl)cyclohexane-   (103)    trans-4-benzylaminomethyl-cis-2-methyl-1-(4-pyridylcarbamoyl)cyclohexane-   (104)    trans-4-(1-benzyloxycarboxamide-1-methylethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (105)    trans-4-benzyloxycarboxamidomethyl-1-(N-methyl-4-pyridylcarbamoyl)cyclohexane-   (106)    trans-4-(1-acetamide-1-methylethyl)-1-(4-pyridylcarbamoyl)cyclohexane-   (107)    trans-N-(6-amino-4-pyrimidyl)-4-aminomethylcyclohexanecarboxamide-   (108)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (109)    (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide-   (110)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxamide-   (111)    trans-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (112)    (+)-trans-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide-   (113)    trans-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxamide-   (114)    (+)-trans-N-(2-amino-4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide-   (115)    trans-N-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (116)    (+)-trans-N-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide-   (117)    trans-N-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxamide-   (118) trans-N-(4-pyrimidinyl)-4-aminomethylcyclohexanecarboxamide-   (119)    trans-N-(3-amino-4-pyridyl)-4-aminomethylcyclohexanecarboxamide-   (120)    trans-N-(7H-imidazo[4,5-d]pyrimidin-6-yl)-4-aminomethylcyclohexanecarboxamide-   (121)    trans-N-(3H-1,2,3-triazolo[4,5-d]pyrimidin-7-yl)-4-aminomethylcyclohexanecarboxamide-   (122)    trans-N-(1-benzyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (123) trans-N-(1H-5-pyrazolyl)-4-aminomethylcyclohexanecarboxamide-   (124)    trans-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (125) trans-N-(4-pyridazinyl)-4-aminomethylcyclohexanecarboxamide-   (126)    trans-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (127)    trans-N-(2-amino-4-pyridyl)-4-aminomethylcyclohexanecarboxamide-   (128)    trans-N-(thieno[2,3-d]pyrimidin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (129)    trans-N-(5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7-yl)-4-aminomethylcyclohexanecarboxamide-   (130)    trans-N-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)-4-aminomethylcyclohexanecarboxamide-   (131)    trans-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxamide-   (132)    trans-N-(2-(1-pyrrolidinyl)-4-pyridyl)-4-aminomethylcyclohexanecarboxamide-   (133)    trans-N-(2,6-diamino-4-pyrimidyl)-4-aminomethylcyclohexane-carboxamide-   (134)    (+)-trans-N-(7-methyl-1,8-naphthyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide-   (135)    trans-N-(1-benzyloxymethylpyrrolo[2,3-b]pyridin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (136)    (+)-trans-N-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide-   (137)    trans-N-benzyl-N-(2-benzylamino-4-pyridyl)-4-(1-amino-1-methylethyl)cyclohexanecarboxamide-   (138)    trans-N-(2-azide-4-pyridyl)-4-aminomethylcyclohexanecarboxamide-   (139)    trans-N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-aminomethylcyclohexanecarboxamide-   (140)    trans-N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxamide-   (141-1)    trans-N-(2-carboxy-4-pyridyl)-4-aminomethylcyclohexanecarboxamide-   (141-2)    (R)-(+)-trans-N-(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide-   (142)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-guanidinomethylcyclohexanecarboxamide-   (143)    trans-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-guanidinomethylcyclohexanecarboxamide-   (144) trans-N-(4-pyridyl)-4-guanidinomethylcyclohexanecarboxamide-   (145)    trans-N-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-4-(guanidinomethyl)cyclohexanecarboxamide-   (146)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2-imidazolin-2-yl)aminomethylcyclohexanecarboxamide-   (147)    trans-N-(1-benzyloxymethylpyrrolo[2,3-b]pyridin-4-yl)-4-guanidinomethylcyclohexanecarboxamide-   (148)    trans-N-(2-amino-4-pyridyl)-4-guanidinomethylcyclohexanecarboxamide-   (149)    trans-N-(1-benzyloxymethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2-imidazolin-2-yl)aminomethylcyclohexanecarboxamide-   (150)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(3-benzylguanidinomethyl)cyclohexanecarboxamide-   (151)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(3-phenylguanidinomethyl)cyclohexanecarboxamide-   (152)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(3-propylguanidinomethyl)cyclohexanecarboxamide-   (153)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(3-octylguanidinomethyl)cyclohexanecarboxamide-   (154)    trans-N-(1-benzyloxymethylpyrrolo[2,3-b]pyridin-4-yl)-4-(2-benzyl-3-ethylguanidinomethyl)cyclohexanecarboxamide-   (155)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(imidazol-2-yl)aminomethylcyclohexanecarboxamide-   (156)    trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(thiazol-2-yl)aminomethylcyclohexanecarboxamide-   (157) (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide-   (158) N-(4-pyridyl)-4-(1-amino-1-methylethyl)benzamide-   (159) N-(4-pyridyl)-4-aminomethyl-2-benzyloxybenzamide-   (160) N-(4-pyridyl)-4-aminomethyl-2-ethoxybenzamide-   (161) (R)-(−)-N-(4-pyridyl)-4-(1-aminoethyl)-3-nitrobenzamide-   (162) (R)-(−)-N-(4-pyridyl)-3-amino-4-(1-aminoethyl)benzamide-   (163) (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)-3-chlorobenzamide-   (164) N-(4-pyridyl)-3-aminomethylbenzamide-   (165)    (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide-   (166)    (R)-(+)-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide-   (167) N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-guanidinomethylbenzamide-   (168) N-(4-pyridyl)-4-guanidinomethylbenzamide-   (169) (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)-3-fluorobenzamide-   (170) N-(4-pyridyl)-4-aminomethylbenzamide-   (171) N-(4-pyridyl)-4-aminomethyl-2-hydroxybenzamide-   (172) N-(4-pyridyl)-4-(2-aminoethyl)benzamide-   (173) N-(4-pyridyl)-4-aminomethyl-3-nitrobenzamide-   (174) N-(4-pyridyl)-3-amino-4-aminomethylbenzamide-   (175) (S)-(−)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide-   (176) (S)-(−)-N-(4-pyridyl)-2-(1-aminoethyl)benzamide-   (177) (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)-2-chlorobenzamide-   (178)    (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-(3-propylguanidino)ethyl)benzamide-   (179)    (R)-(−)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)-3-azidebenzamide-   (180) (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)-2-nitrobenzamide-   (181) (R)-(−)-N-(4-pyridyl)-4-(1-aminoethyl)-3-ethoxybenzamide-   (182)    (R)-(+)-N-(3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide-   (183)    (R)-(+)-N-(3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)-3-azidebenzamide-   (184) (R)-(−)-N-(4-pyridyl)-4-(1-aminoethyl)-3-hydroxybenzamide-   (185)    N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-guanidinomethyl-3-nitrobenzamide-   (186)    (R)-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-guanidinoethyl)-3-nitrobenzamide-   (187)    (R)-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-aminoethyl)-2-nitrobenzamide-   (188) N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-guanidinobenzamide-   (189)    (R)-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-aminoethyl)-3-nitrobenzamide-   (190)    (R)-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-guanidinoethyl)benzamide-   (191)    N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-amino-2-hydroxyethyl)benzamide-   (192)    N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-aminomethyl-3-nitrobenzamide-   (193) N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide-   (194) N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-piperidinecarboxamide-   (195)    N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1-aminoacetyl-4-piperidinecarboxamide-   (196)    N-(1-methoxymethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-piperidinecarboxamide-   (197)    N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide-   (198)    N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-phenylethyl)-4-piperidinecarboxamide-   (199)    N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-amidino-4-piperidinecarboxamide-   (200)    N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(3-phenylpropyl)-4-piperidinecarboxamide-   (201)    N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-benzyl-4-piperidinecarboxamide-   (202)    N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1-(2-phenylethyl)-4-piperidinecarboxamide-   (203)    N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1-(3-phenylpropyl)-4-piperidinecarboxamide

Preferred are compounds (80), (109), (110), (112), (115), (142), (143),(144), (145), (153), (157), (163), (165), (166) and (179).

The compound having a Rho kinase inhibitory activity may be apharmaceutically acceptable acid addition salt, wherein the acid isexemplified by inorganic acid such as hydrochloric acid, hydrobromicacid, sulfuric acid and the like, and organic acid such asmethanesulfonic acid, fumaric acid, maleic acid, mandelic acid, citricacid, tartaric acid, salicylic acid and the like. A compound having acarboxylic group can be converted to a salt with a metal such as sodium,potassium, calcium, magnesium, aluminum and the like, a salt with anamino acid such as lysine and the like. Further, monohydrate, dihydrate,1/2 hydrate, 1/3 hydrate, 1/4 hydrate, 2/3 hydrate, 3/2 hydrate, 6/5hydrate and the like are encompassed in the present invention.

The compound of the formula (I) can be synthesized by a method describedin, for example, JP-A-62-89679, JP-A-3-218356, JP-A-5-194401,JP-A-6-41080, WO95/28387, WO98/06433 and the like.

When the above-mentioned compound having a Rho kinase inhibitoryactivity has an optical isomer, its racemate or cis-trans isomers, allof them can be used in the present invention. These isomers can beisolated by a conventional method or can be produced using startingmaterials of the isomers.

A compound having a Rho kinase inhibitory activity, particularly, acompound of the formula (I), an isomer thereof and/or a pharmaceuticallyacceptable acid addition salt thereof have a preventive and therapeuticeffect on interstitial pneumonia and pulmonary fibrosis in mammalsinclusive of human, cow, horse, dog, mouse, rat and the like. Therefore,they can be used as an agent for the prophylaxis and treatment ofvarious types of interstitial pneumonia and pulmonary fibrosis.

The agent for the prophylaxis and treatment of interstitial pneumoniaand pulmonary fibrosis of the present invention is administered orallyor parenterally.

For example, the compound having a Rho kinase inhibitory activity ismixed with a pharmaceutically acceptable carrier (e.g., excipient,binder, disintegrator, corrective, corrigent, emulsifier, diluent,solubilizer and the like) to give a pharmaceutical composition or apharmaceutical preparation in the form of tablet, pill, powder, granule,capsule, troche, syrup, liquid, emulsion, suspension, injection (e.g.,liquid, suspension and the like), suppository, inhalant, percutaneousabsorber, eye drop, eye ointment and the like in the form suitable fororal or parenteral preparation.

When preparing a solid preparation, additives such as sucrose, lactose,cellulose sugar, D-mannitol, maltitol, dextran, starches, agar,arginates, chitins, chitosans, pectines, tragacanth gum, gum arabic,gelatins, collagens, casein, albumin, calcium phosphate, sorbitol,glycine, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose, hydroxypropylmethylcellulose, glycerol,polyethyleneglycol, sodium hydrogencarbonate, magnesium stearate, talcand the like are used. Tablets can be applied with a typical coating,where necessary, to give sugar coated tablets, enteric tablets,film-coated tablets, two-layer tablets and multi-layer tablets.

When preparing a semi-solid preparation, animal and plant fats and oils(e.g., olive oil, corn oil, castor oil and the like), mineral fats andoils (e.g., petrolatum, white petrolatum, solid paraffin and the like),wax (e.g., jojoba oil, carnauba wax, bee wax and the like), partly orentirely synthesized glycerol fatty acid esters (e.g., lauric acid,myristic acid, palmitic acid and the like), and the like are used.

Examples of commercially available products of these include Witepsol(manufactured by Dynamitnovel Ltd.), Farmazol (NOF Corporation) and thelike.

When preparing a liquid preparation, an additive, such as sodiumchloride, glucose, sorbitol, glycerol, olive oil, propylene glycol,ethyl alcohol and the like, is used. When preparing an injection, asterile aqueous solution such as physiological saline, isotonicsolution, oil (e.g., sesame oil and soybean oil) and the like are used.Where necessary, a suitable suspending agent such as sodiumcarboxymethylcellulose, nonionic surfactant, solubilizer (e.g., benzylbenzoate and benzyl alcohol), and the like can be concurrently used.Moreover, when an eye drop is prepared, an aqueous liquid or solution isused, which is particularly a sterile injectable aqueous solution. Theeye drop can appropriately contain various additives such as buffer(borate buffer, acetate buffer, carbonate buffer and the like arepreferable for reducing irritation), isotonicity agent, solubilizer,preservative, thickener, chelating agent, pH adjusting agent (generally,pH is preferably adjusted to about 6-8.5) and aromatic.

The dose of the compound having a Rho kinase inhibitory activity, whichis the active ingredient of these preparations, is 0.1-100 wt %,suitably 1-50 wt %, of the preparation. While the dose varies dependingon the symptom, body weight, age and the like of patients, it isgenerally about 1-500 mg a day for an adult, which is administered onceto several times a day.

EXAMPLES

The present invention is explained in detail by referring to formulationexamples and pharmacological action. The present invention is notlimited in any way by the examples.

Formulation Example 1

Tablet

compound of the present invention 10.0 mg Lactose 50.0 mg Corn starch20.0 mg Crystalline cellulose 29.7 mg Polyvinylpyrrolidone K30 5.0 mgTalc 5.0 mg Magnesium stearate 0.3 mg 120.0 mg

The compound of the present invention, lactose, corn starch andcrystalline cellulose were mixed, kneaded with polyvinylpyrrolidone K30paste solution and passed through a 20-mesh sieve for granulation. Afterdrying at 50° C. for 2 hours, the granules were passed through a 24-meshsieve, and talc and magnesium stearate were added. Using a φ7 mm punch,tablets weighing 120 mg per tablet were prepared.

compound of the present invention 10.0 mg Lactose 70.0 mg Corn starch35.0 mg Polyvinylpyrrolidone K30 2.0 mg Talc 2.7 mg Magnesium stearate0.3 mg 120.0 mg

The compound of the present invention, lactose and corn starch weremixed, kneaded with polyvinylpyrrolidone K30 paste solution and passedthrough a 20-mesh sieve for granulation. After drying at 50° C. for 2hours, the granules were passed through a 24-mesh sieve and talc andmagnesium stearate were added. The mixture was filled in hard capsules(No. 4) to give capsules weighing 120 mg.

The pharmacological action of the pharmaceutical agent of the presentinvention is explained in the following by referring to ExperimentalExamples.

In the following Experimental Examples, a compound having a Rho kinaseinhibitory activity:(+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane 2HCl.1H₂O(hereinafter Y-27632) was used. Y-27632 was dissolved and diluted inphysiological saline to achieve a predetermined concentration.

Experimental Example 1

Expression of ROCK-II Gene in Bleomycin-induced Interstitial Pneumonia(Pulmonary Fibrosis) Model

(Method)

Female C57BL/6 mice (about 15 g, 6-week-old) in 4 mice per group (n=4)were intraperitoneally administered with bleomycin 5 times a day everyother day (total dose: 200 mg/kg) to prepare a model withbleomycin-induced interstitial pneumonia (pulmonary fibrosis).

The expression of ROCK-II gene in the lung at 7, 14, 21 and 40 daysafter the start of the bleomycin administration was measured, and so wasthe value of an animal free of bleomycin administration. The amount ofthe expression of the ROCK-II gene was measured according to a real timequantitative RT-PCR method. As the primer, the following sequence wasused [forward: CATGGTGCATTGCGACACA (SEQ ID No. 1), reverse:TCGCCCATAGTAACATCACCT (SEQ ID No. 2)]. The amount of expression of theROCK-II gene was expressed relatively in [(Rock-II m RNA)/(GAPDH m RNA)]using the expression amount of GAPDH (glyceraldehyde-3-phosphatedehydrogenase) gene as a standard. The results are shown in mean±SEM(n=4). For the test, (Satical analysis was performed One-way ANOVA testfollowed by Fisher's least significance test) was performed.

(Results)

The expression amount of ROCK-II gene of the bleomycin administrationgroup was significantly high at day 7 and day 21 as compared to thebleomycin non-administration group (FIG. 1). Particularly, it increasedto about 9 times the amount of the bleomycin non-administration group atday 21.

Experimental Example 2

Effect in Bleomycin-induced Interstitial Pneumonia (Pulmonary Fibrosis)Model

Using the bleomycin-induced interstitial pneumonia (pulmonary fibrosis)model prepared in Experimental Example 1, the effect of the presentinvention on induced interstitial pneumonia (pulmonary fibrosis) wasexamined.

(Method)

Y-27632 was intraperitoneally administered immediately before bleomycinadministration from the first day of bleomycin administration (0th) today 8 (5th administration), and thereafter until day 40, by way of asingle, alternate-day administration. At day 40, the level of fibrosiswas checked by hydroxyproline content and tissue staining. Thehydroxyproline content was measured according to the report of Tran etal. (Tran et al., J. Clin. Invest., 99: 608-617, 1997). The degree offibrosis by tissue staining was evaluated by the Aschcroft score(Aschcroft et al., J. Clin. Pathol., 41: 467-70, 1988).

(Results)

1. Hydroxyproline Content

Y-27632 dose-dependently suppressed the increase of hydroxyprolinecontent due to bleomycin administration (Table 1). The suppressionpercentage was calculated based on the bleomycin alone administrationgroup as 0% suppression, and the physiological saline administrationgroup as 100% suppression.

TABLE 1 Suppression (%) bleomycin + Y-27632 (100 μg/kg) 53.8 + Y-27632(10 μg/kg) 38.6 + Y-27632 (1 μg/kg) 30.0 + Y-27632 (0.1 μg/kg) 28.2 +Y-27632 (0.01 μg/kg) −10.6 Y-27632 alone (1000 μg/kg) 92.12. Measurement of Pulmonary Fibrosis Level by Tissue Staining

Y-27632 suppressed the increase of Aschcroft score due to bleomycinadministration at the dose of not less than 10 μg/kg (Table 2). In theTable, *:p<0.05, **:p<0.01.

TABLE 2 Aschcroft score (mean ± standard error) bleomycin alone 3.54 ±0.43 bleomycin + Y-27632 (0.1 μg/kg) 2.79 ± 0.26 + Y-27632 (10 μg/kg)1.85 ± 0.26** + Y-27632 (100 μg/kg) 1.98 ± 0.41* Y-27632 alone (1000μg/kg) 1.33 ± 0.21 physiological saline 1.12 ± 0.32 administration group

Experimental Example 3

Effect on the Number of Inflammatory cells in Bronchoalveolar LavageFluid (BALF) in Bleomycin-induced Interstitial Pneumonia (PulmonaryFibrosis) Model

(Method)

Using the pulmonary fibrosis model administered with bleomycin as inExperimental Example 1, the effect of Y-27632 on the number of variousinflammatory cells in BALF was examined.

The dose of Y-27632 was administered every other day at the lo dose of100 μg/kg in the same manner as in Experimental Example 2. BALF wasrecovered at day 7, day 14, day 21 and day 40 from the start of thebleomycin administration, and the number of total cells, macrophages,lymphocytes and neutrophils was counted (n=5). The number of total cellswas measured by a hemocytometer. Smear preparations of the various cellsin BALF were prepared by cytospin (Auto Smer CF-12D, Chiyoda seisakusho,Tokyo, Japan), stained with May-Gruenwald and subjected to the countingunder a microscope.

(Results)

The results are shown in FIG. 2, wherein □ shows a group (BLM group)subjected to bleomycin administration and alternate-day administrationof physiological saline, ∘ shows a group (Y-27632 group) subjected tobleomycin administration and alternate-day administration of Y-27632,and Δ shows a group (Normal group) subjected to alternate-dayadministration of physiological saline but without bleomycinadministration. The results are shown in mean±SEM (n=5). For the test,(Satical analysis was performed One-way ANOVA test followed by Fisher'sleast significance test) was performed (*p<0.05; BLM group vs Y-27632group) (§p<0.05; BLM group vs Normal group) (+p<0.05; Y-27632 group vsNormal group).

The lymphocyte (c) counts did not show a significant difference among 3groups. The Y-27632 group showed significantly lower results than BLMgroup in the number of total cells (a), macrophages (b) and neutrophils(d).

Therefrom it was clarified that the treatment with Y-27632 suppressesinfiltration of inflammatory cells into BALF.

Experimental Example 4

Effect on Cell Chemotaxis

(Results)

Mouse alveolar macrophage-derived cell line (MH-S cell), fibroblast(NIH3T3 cell) and mouse neutrophil were used. Casein wasintraperitoneally administered to the mouse and the mouse neutrophil wasisolated from ascites thereof after 6 h. The cell chemotaxis wasmeasured by a Boyden chamber (chemotaxicell, KURABO, Japan). The poresize of the filter used was 5 μm for MH-S cell and neutrophil, and 8 μmfor NIH3T3 cell. As a chemotactic factor, lipopolysaccharide (LPS,E.coli: B-4, Sigma, St Louis, Mo., USA) was used for MH-S cell, mouseinterleukin 1β (IL-1β, Genzyme/techne, USA) was used for neutrophil, anda platelet activating factor (PDGF-BB, UBI, Lake Placid, USA) was usedfor NIH3T3 cell. The chemotactic factors were added to a lower layer andY-27632 were added to a higher layer at various concentrations. Thereaction was carried out at 37° C. for 120 min for MH-S cell and NIH3T3cell and 37° C. for 90 min for neutrophil. After the completion of thereaction, migrated cells were stained with Giemsa (Muto, CO., Ltd,Japan) and the cells were counted. The value is in mean±SEM.

(Results)

In MH-S cells, Y-27632 suppressed the migration by LPS (1 μg/ml) in aconcentration-dependent manner, and the IC₅₀ value thereof was 4.8±2.0μM (n=6) (FIG. 3(a)). In neutrophils, Y-27632 suppressed the migrationby IL-1. (5 ng/ml) in a concentration-dependent manner and the IC₅₀value thereof was 8.4±2.1 μM (n=6) (FIG. 3(b)). In NIH3T3 cells, Y-27632suppressed the migration by PDGF-BB (10 ng/ml) in aconcentration-dependent manner, and the IC₅₀ value thereof was 1.6±0.5μM (n=6) (FIG. 3(c)).

INDUSTRIAL APPLICABILITY

From the above-mentioned Formulation Example and Experimental Exampleand pharmacological tests, it is clear that a compound having a Rhokinase inhibitory activity shows a preventive and therapeutic effect oninterstitial pneumonia and pulmonary fibrosis, and is useful as an agentfor the prevention and treatment of interstitial pneumonia and pulmonaryfibrosis.

The bleomycin-induced interstitial pneumonia (pulmonary fibrosis) modelused in the present invention showed a significantly higher expressionamount of ROCK-II gene, and activation of the ROCK-II gene was suggestedto be involved in the expression of interstitial pneumonia and pulmonaryfibrosis.

Moreover, it was confirmed that the compound having a Rho kinaseinhibitory activity of the present invention suppresses infiltration ofvarious inflammatory cells into tracheal alveolar, and at the same time,suppresses migration of each cell of macrophage-derived cell, fibroblastand neutrophil, in the bleomycin-induced interstitial pneumonia(pulmonary fibrosis) model used in the present invention.

This application is based on a patent application No. 81072/1999 filedin Japan, the content of which is hereby incorporated by reference.

SEQUENCE LISTING FREE TEXT

-   SEQ ID NO: 1: Oligonucleotide designed to act as sequencing primer    (forward).-   SEQ ID NO: 2: Oligonucleotide designed to act as sequencing primer    (reverse).

1. A method for treatment of interstitial pneumonia and pulmonaryfibrosis, which comprises administering an effective amount of acompound having a Rho kinase inhibitory activity to a patient, whereinthe compound having a Rho kinase inhibitory activity is an amidecompound of the following formula (I),

wherein Ra is a group of the formula

in the formulas (a) and (b), R is hydrogen, alkyl, or cycloalkyl,cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituenton the ring, or a group of the formula

 wherein R⁶ is hydrogen, alkyl or the formula: —NR⁸R⁹ wherein R⁸ and R⁹are the same or different and each is hydrogen, alkyl, aralkyl orphenyl, R⁷ is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R⁶and R⁷ in combination show a group forming a heterocycle optionallyhaving, in the ring, oxygen atom, sulfur atom or optionally substitutednitrogen atom, R¹ is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl,phenyl or aralkyl, which optionally has a substituent on the ring, or Rand R¹ in combination form, together with the adjacent nitrogen atom, agroup forming a heterocycle optionally having, in the ring, oxygen atom,sulfur atom or optionally substituted nitrogen atom, R² is hydrogen oralkyl, R³ and R⁴ are the same or different and each is hydrogen, alkyl,aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy,aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy,alkoxycarbonyl, carbamoyl, alkylcarbamoyl or azide, and A is a group ofthe formula

 wherein R¹⁰ and R¹¹ are the same or different and each is hydrogen,alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, orR¹⁰ and R¹¹ show a group which forms cycloalkyl in combination and l, mand n are each 0 or an integer of 1-3, in the formula (c), L ishydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl,tetrahydrofurfuryl, carbamoylalkyl, phthalimidoalkyl, amidino or a groupof the formula

 wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl,hydroxyalkyl, alkanoyloxy-alkyl, alkoxycarbonylalkyl, α-aminobenzyl,furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl, Q¹ ishydrogen, halogen, hydroxy, aralkyloxy or thienylmethyl, W is alkylene,Q² is hydrogen, halogen, hydroxy or aralkyloxy, X is alkylene, Q³ ishydrogen, halogen, hydroxy, alkoxy, nitro, amino, 2,3-dihydrofuryl or5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl; and Y is a single bond,alkylene or alkenylene, and in the formula (c), a broken line is asingle bond or a double bond, and R⁵ is hydrogen, hydroxy, alkoxy,alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy; Rb is ahydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- ordialkylaminoalkyl; and Rc is an optionally substituted heterocyclecontaining nitrogen, an isomer thereof and/or a pharmaceuticallyacceptable acid addition salt thereof.
 2. The method for treatment ofinterstitial pneumonia and pulmonary fibrosis of claim 1, wherein thecompound having a Rho kinase inhibitory activity is an amide compound ofthe following formula (I′)

wherein Ra′ is a group of the formula

 wherein R′ is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenylor aralkyl, which optionally has a substituent on the ring, R¹ ishydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl,which optionally has a substituent on the ring, or R′ and R¹ incombination form, together with the adjacent nitrogen atom, a groupforming a heterocycle optionally having, in the ring, oxygen atom,sulfur atom or optionally substituted nitrogen atom, R² is hydrogen oralkyl, R³ and R⁴ are the same or different and each is hydrogen, alkyl,aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy,aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy,alkoxycarbonyl, carbamoyl, alkylcarbamoyl or azide, and A is a group ofthe formula

 wherein R¹⁰ and R¹¹ are the same or different and each is hydrogen,alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, orR¹⁰ and R¹¹ show a group which forms cycloalkyl in combination and l, mand n are each 0 or an integer of 1-3, Rb is a hydrogen, an alkyl, anaralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and Rc is anoptionally substituted heterocycle containing nitrogen, an isomerthereof and/or a pharmaceutically acceptable acid addition salt thereof.3. The method for treatment of interstitial pneumonia and pulmonaryfibrosis of claim 1, wherein the compound having a Rho kinase inhibitoryactivity is a compound selected from the group consisting of(+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane,(+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4--(1-aminoethyl)cyclohexanecarboxamide,(R)-(+)-N-(4-pyridyl)-4(1-aminoethyl)benzamide and(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide,and/or a pharmaceutically acceptable acid addition salt thereof.
 4. Themethod for treatment of interstitial pneumonia and pulmonary fibrosis ofclaim 1, wherein the compound having a Rho kinase inhibitory activity isa (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, and/or apharmaceutically acceptable acid addition salt thereof.
 5. A method forthe production of an agent for treatment of interstitial pneumonia andpulmonary fibrosis, which comprises mixing a compound having a Rhokinase inhibitory activity with a pharmaceutically acceptable carrier,wherein the compound having a Rho kinase inhibitory activity is an amidecompound of the following formula (I)

wherein Ra is a group of the formula

 in the formulas (a) and (b), R is hydrogen, alkyl, or cycloalkyl,cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituenton the ring, or a group of the formula

 wherein R⁶ is hydrogen, alkyl or formula: —NR⁸R⁹ wherein R⁸ and R⁹ arethe same or different and each is hydrogen, alkyl, aralkyl or phenyl, R⁷is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R⁶ and R⁷ incombination show a group forming a heterocycle optionally having, in thering, oxygen atom, sulfur atom or optionally substituted nitrogen atom,R¹ is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl oraralkyl, which optionally has a substituent on the ring, or R and R¹ incombination form, together with the adjacent nitrogen atom, a groupforming a heterocycle optionally having, in the ring, oxygen atom,sulfur atom or optionally substituted nitrogen atom, R² is hydrogen oralkyl, R³ and R⁴ are the same or different and each is hydrogen, alkyl,aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy,aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy,alkoxycarbonyl, carbamoyl, alkylcarbamoyl or azide, and A is a group ofthe formula

 wherein R¹⁰ and R¹¹ are the same or different and each is hydrogen,alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, orR¹⁰ and R¹¹ show a group which forms cycloalkyl in combination and l, mand n are each 0 or an integer of 1-3, in the formula (c), L ishydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl,tetrahydrofurfuryl, carbamoylalkyl, phthalimidoalkyl, amidino or a groupof the formula

 wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl,hydroxyalkyl, alkanoyloxy-alkyl, alkoxycarbonylalkyl, α-aminobenzyl,furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl, Q¹ ishydrogen, halogen, hydroxy, aralkyloxy or thienylmethyl, W is alkylene,Q² is hydrogen, halogen, hydroxy or aralkyloxy, X is alkylene, Q³ ishydrogen, halogen, hydroxy, alkoxy, nitro, amino, 2,3-dihydrofuryl or5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl; and Y is a single bond,alkylene or alkenylene, and in the formula (c), a broken line is asingle bond or a double bond, and R⁵ is hydrogen, hydroxy, alkoxy,alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy; Rb is ahydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- ordialkylaminoalkyl; and Rc is an optionally substituted heterocyclecontaining nitrogen, an isomer thereof and/or a pharmaceuticallyacceptable acid addition salt thereof.
 6. The method of claim 5, whereinthe compound having a Rho kinase inhibitory activity is an amidecompound of the following formula (I′)

wherein Ra′ is a group of the formula

 wherein R′ is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenylor aralkyl, which optionally has a substituent on the ring, R¹ ishydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl,which optionally has a substituent on the ring, or R′ and R¹ incombination form, together with the adjacent nitrogen atom, a groupforming a heterocycle optionally having, in the ring, oxygen atom,sulfur atom or optionally substituted nitrogen atom, R² is hydrogen oralkyl, R³ and R⁴ are the same or different and each is hydrogen, alkyl,aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy,aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy,alkoxycarbonyl, carbamoyl, alkylcarbamoyl or azide, and A is a group ofthe formula

 wherein R¹⁰ and R¹¹ are the same or different and each is hydrogen,alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, orR¹⁰ and R¹¹ show a group which forms cycloalkyl in combination and l, mand n are each 0 or an integer of 1-3, Rb is a hydrogen, an alkyl, anaralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and Rc is anoptionally substituted heterocycle containing nitrogen, an isomerthereof and/or a pharmaceutically acceptable acid addition salt thereof.7. The method of claim 5, wherein the compound having a Rho kinaseinhibitory activity is a compound selected from the group consisting of(+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane,(+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide,(R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and(R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide,and/or a pharmaceutically acceptable acid addition salt thereof.
 8. Themethod of claim 5, wherein the compound having a Rho kinase inhibitoryactivity is a(+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, and/or apharmaceutically acceptable acid addition salt thereof.